1. Field of the Invention
This invention relates to new anthracycline glycoside antitumor antibiotics and to their production. More particularly, it relates to new antitumor antibiotic substances designated aclacinomycins A and B and to processes for the preparation thereof by the fermentation of a strain Streptomyces galilaeus (e.g., MA144-M1), to methods for their recovery and purification, and to their application as cancer chemotherapeutic agents.
2. Description of the Prior Art
A number of anthracycline glycosides have been found in the cultured broth of Streptomyces. Among them, daunomycin and adriamycin are particularly being watched with keen interest in the field of cancer chemotherapy and have already been applied clinically for human cancers. In the continuation of the study of antitumor antibiotics, the present inventors discovered new compounds and after characterization and purification based on their physico-chemical properties, they confirmed that these antibiotics now named aclacinomycin A and B are new compounds which show low cardiotoxicity and potent antitumor activity in various animal tumors, and they established processes and methods for their production and isolation.
Farmitalia's U.S. patent on adriamycin (B-106FI; 14-hydroxy-daunomycin; INN is Doxorubicin) is U.S. Pat. No. 3,590,028 claiming the product by structure and disclosing its direct fermentation by S. peuceticus var. caesius. Farmitalia also issued U.S. 3,803,124 on chemical conversion of daunomycin to adriamycin; for direct fermentation of daunomycin (as antibiotic FI 1762) by S. peuceticus see U.K. Pat. No. 1,003,383.
Farmitalia's daunomycin (U.K. Pat. No. 1,003,383) may be the same as Rhone-Poulenc's 13057 R.P. (formerly rubidomycin and now Daunoribicin (U.K. Pat. No. 985,598; 1,188,262; 1,241,750 and see U.S. Pat. No. 3,616,242) and is "probably" identical with Ciba's danubomycin (U.S. Pat. No. 3,092,550; U.K. Pat. No. 901,830). See also U.S. Pat. No. 3,686,163 on dihydrodaunomycin.
Cinerubin A and cinerubin B are disclosed in U.K. Pat. No. 846,130 and see also U.S. Pat. No. 3,864,480 and KellerSchierlein et al., Antimicrobial Agents and Chemotherapy, page 68 (1970) and Chemical Abstracts, 54, 1466i (1960).
For further illustrative and summary disclosures of anthracycline antibiotics see Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-chief, University Park Press, State College, Pennsylvania, U.S.A. (1967) as follows:
______________________________________ Antibiotic Page Number ______________________________________ Aklavin 111 Cinerubin A 220 Cinerubin B 221 Danubomycin 242 Daunomycin 243 -Pyrromycin 542 Rhodomycin A,B 561 Rubidomycin 574 ______________________________________
The textbook Antibiotics, Volume 1, Mechanism of Action, edited by David Gottlieb and Paul D. Shaw, Springer - Verlag New York, Inc., N.Y., N.Y. (1967) at pages 190-210 contains a review by A. DiMarco entitled Daunomycin and Related Antibiotics.
Information Bulletin, No. 10, International Center of Information of Antibiotics, in collaboration with WHO, December, 1972, Belgium, reviews anthracyclines and their derivatives.
For a description of Streptomyces galilaeus see Arch. fur Mikrobiol., 31, 356 (1958) and International Journal of Systematic Bacteriology, 22, 298 (1972).
This specification on page 37 refers to disclosures by K. Eckardt et al. on galirubins; see Chemical Abstracts 64, 3896g and 67, 90573z.